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Chronic nicotine and synaptic transmission in brainstem respiratory neurons

脑干呼吸神经元的慢性尼古丁和突触传递

基本信息

批准号：
10401834
负责人：
Ralph Frank Fregosi
金额：
$ 37.4万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401834
关键词：
ARHGEF5 gene Acetylcholine Action Potentials Acute Adolescence Age Animals Attenuated Birth Brain Brain Stem Breathing Carbon Dioxide Cells Chronic Data Deglutition Dendrites Development Devices Electronic cigarette Electrophysiology (science)Experimental Designs Exposure to Glutamates Glycine Goals Growth Homeostasis Human Milk Hypercapnia Immunohistochemistry In Vitro Injections Life Longevity Maintenance Mastication Measurement Membrane Membrane Potentials Mothers Motor Motor Neurons Muscle Nervous system structure Neuroanatomy Neurons Neurotransmitter Receptor Neurotransmitters Newborn Animals Nicotine Nicotinic Receptors Outcome Output Pattern Physicians Physiological Play Plethysmography Process Progress Reports Property Protocols documentation Pump Rattus Resistance Respiration Role Smokeless Structure Synapses Synaptic Transmission System Techniques Testing Time Tongue Weaning Work critical period drinking water electronic cigarette use experimental study gamma-Aminobutyric Acid gender difference hookah in utero in vivo neonatal period nervous system development nicotine exposure nicotine gum nicotine patch nicotine use patch clamp postnatal postsynaptic prenatal prenatal cigarette smoking prenatal exposure prenatal nicotine exposure presynaptic receptor expression relating to nervous system respiratory response sex social stressor suckling voltage

项目摘要

Despite a growing body of evidence showing that in utero nicotine exposure leads to aberrant development of brainstem neurons involved in the maintenance of key homeostatic functions such as breathing, the consumption of nicotine via smokeless nicotine delivery devices (e.g., e-cigarettes, water pipes, nicotine patches or gum) more than doubled between 2008-2012. A particular concern is raised by recent studies showing that 30% of pregnant smokers were advised to use nicotine patches or gum by their physician. To date, the majority of the data on nicotine exposure and development of brainstem neurons has focused on how in utero exposure alters the brains of very young neonatal animals. As a result, we do not know if the changes observed with in utero exposure resolve or persist with maturation, or worsen if exposure continues after birth. The specific objective of this application is to test the hypothesis that prenatal and/or postnatal exposure to nicotine alters the structure and function of brainstem neurons that control the muscles of the tongue (hypoglossal motor neurons, XIIMNs), using an in vitro approach, as well as the breathing-related control of the tongue muscles, using an in vivo approach. The tongue muscles participate in breathing, swallowing, suckling and mastication, and therefore are critical for organismal homeostasis. A key focus is whether abnormal development of the tongue muscle motor system is worsened if nicotine exposure continues after birth, or if the alterations persist or are attenuated if exposure ends at weaning. Animals (rats) will be studied at key developmental time points, including the early neonatal period (postnatal day 1 (P1) - P5); the putative critical period for development of brainstem neurons (P10 - P12); the end of adolescence when brain maturation is largely complete (P50 – P60); and after sexual and social maturity (4 – 6 months). Specific Aims: We will use neuroanatomy, immunohistochemistry, patch clamp electrophysiology and in vivo plethysmography and EMG recordings to examine how prenatal and/or postnatal nicotine exposure alters: 1) the dendrite branching pattern and the expression of inhibitory (GABA, glycine) and excitatory (glutamate) neurotransmitter receptors on XIIMNs; 2) development of important neuron membrane properties (resting potential, voltage threshold for spike initiation, etc.), the cell's response to excitatory and inhibitory neurotransmitters; 3) development of the breathing pattern and the function of tongue muscles during normal, quiet breathing and when breathing is increased in response to an acute nicotine challenge or by increasing inspired carbon dioxide. The proposed experiments will result in a comprehensive understanding of how in utero and life-long nicotine exposure alters development of brainstem motoneurons that are critical for survival.

尽管越来越多的证据表明，在子宫内接触尼古丁会导致异常脑干神经元的发育参与维持关键的体内平衡功能，如呼吸，通过无烟尼古丁输送装置(例如，电子烟，水烟、尼古丁贴片或口香糖)在2008-2012年间翻了一番以上。一个特别令人担忧的问题最近的研究表明，30%的怀孕吸烟者被建议使用尼古丁医生提供的贴片或口香糖。到目前为止，大多数关于尼古丁暴露和脑干神经元的发展主要集中在子宫内暴露如何改变大脑。幼小的新生动物。因此，我们不知道在子宫内暴露时观察到的变化解决或坚持成熟，或恶化，如果出生后继续暴露。具体目标这一应用的目的是检验这样一个假设，即出生前和/或出生后接触尼古丁会改变控制舌肌(舌下肌)的脑干神经元的结构和功能运动神经元，XIIMN)，使用体外方法，以及与呼吸有关的控制舌部肌肉，使用活体方法。舌肌参与呼吸、吞咽、哺乳和咀嚼，因此对生物体的动态平衡至关重要。一个主要关注点是如果接触尼古丁，舌肌运动系统的异常发育是否恶化如果在出生后继续，或者如果改变持续或如果暴露在断奶时结束则减弱。动物(大鼠)将在关键的发育时间点进行研究，包括早期新生儿期。 (出生后第1天(P1)-P5)；推测为脑干神经元发育的关键期(P10- 青春期结束，此时大脑基本成熟(P50-P60)；之后性成熟和社交成熟(4-6个月)。具体目标：我们将使用神经解剖学，免疫组织化学、膜片钳电生理学及体内体积描记和肌电检查产前和/或出生后尼古丁暴露如何改变的录音：1)树突分枝模式与抑制性(GABA、甘氨酸)和兴奋性(谷氨酸)的表达 XIIMN上的神经递质受体；2)重要神经元膜特性的发展 (静息电位、启动尖峰的电压阈值等)，细胞对兴奋性和抑制性神经递质；3)呼吸模式和舌头功能的发展肌肉在正常、安静的呼吸中以及当呼吸增加时响应急性呼吸尼古丁挑战或通过增加吸入的二氧化碳。拟议的实验将导致全面了解宫内和终生尼古丁暴露如何改变糖尿病的发生对生存至关重要的脑干运动神经元。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Developmental nicotine exposure disrupts dendritic arborization patterns of hypoglossal motoneurons in the neonatal rat.

发育过程中的尼古丁暴露会破坏新生大鼠舌下运动神经元的树突状树枝化模式。

DOI：
10.1002/dneu.22379
发表时间：
2016
期刊：
Developmental neurobiology
影响因子：
3
作者：
Powell,GregoryL;Gaddy,Joshua;Xu,Fei;Fregosi,RalphF;Levine,RichardB
通讯作者：
Levine,RichardB

Current injection and receptor-mediated excitation produce similar maximal firing rates in hypoglossal motoneurons.

电流注射和受体介导的兴奋在舌下运动神经元中产生相似的最大放电率。

DOI：
10.1152/jn.00848.2015
发表时间：
2016
期刊：
Journal of neurophysiology
影响因子：
2.5
作者：
Wakefield,HilaryE;Fregosi,RalphF;Fuglevand,AndrewJ
通讯作者：
Fuglevand,AndrewJ

Developmental nicotine exposure alters AMPA neurotransmission in the hypoglossal motor nucleus and pre-Botzinger complex of neonatal rats.

DOI：
10.1523/jneurosci.3711-12.2013
发表时间：
2013-02-06
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Jaiswal SJ;Pilarski JQ;Harrison CM;Fregosi RF
通讯作者：
Fregosi RF

Influence of developmental nicotine exposure on glutamatergic neurotransmission in rhythmically active hypoglossal motoneurons.

发育期尼古丁暴露对节律性活跃舌下运动神经元谷氨酸能神经传递的影响。